Daily Endocrinology Research Analysis
Two phase 3a RCTs (COMBINE 1 and COMBINE 3) show that once‑weekly IcoSema, a fixed‑ratio co‑formulation of insulin icodec and semaglutide, is superior to icodec alone and non‑inferior to basal‑bolus therapy in adults with type 2 diabetes. A Cell Metabolism study integrates physiology and genetics to model inter‑individual variability in satiation and develop a genetic risk score with potential to predict obesity treatment responses.
Summary
Two phase 3a RCTs (COMBINE 1 and COMBINE 3) show that once‑weekly IcoSema, a fixed‑ratio co‑formulation of insulin icodec and semaglutide, is superior to icodec alone and non‑inferior to basal‑bolus therapy in adults with type 2 diabetes. A Cell Metabolism study integrates physiology and genetics to model inter‑individual variability in satiation and develop a genetic risk score with potential to predict obesity treatment responses.
Research Themes
- Once-weekly fixed-ratio insulin–GLP-1RA combinations for type 2 diabetes
- Treat-to-target trial designs and global multicentre RCTs
- Genetic and physiological determinants of satiation and treatment response in obesity
Selected Articles
1. Once‑weekly IcoSema versus once‑weekly insulin icodec in type 2 diabetes management (COMBINE 1): an open‑label, multicentre, treat‑to‑target, randomised, phase 3a trial.
In a 52‑week, open‑label, treat‑to‑target, phase 3a RCT across 20 countries (n=1291), once‑weekly IcoSema (icodec+semaglutide) achieved superior HbA1c reduction versus once‑weekly icodec alone in adults with type 2 diabetes inadequately controlled on daily basal insulin. The trial supports efficacy of a simplified once‑weekly fixed‑ratio regimen.
Impact: Demonstrates superiority of a once‑weekly fixed‑ratio insulin–GLP‑1RA over weekly basal insulin alone, potentially shifting intensification strategies for insulin‑treated type 2 diabetes.
Clinical Implications: For adults inadequately controlled on daily basal insulin, once‑weekly IcoSema may provide greater glycaemic improvement with a simplified regimen, supporting consideration of fixed‑ratio insulin–GLP‑1RA co‑formulations in treatment pathways.
Key Findings
- 52‑week, open‑label, treat‑to‑target, phase 3a RCT across 192 sites in 20 countries.
- 1291 participants randomized: IcoSema (n=646) vs icodec (n=645).
- IcoSema showed superiority to icodec alone in HbA1c change at week 52.
Methodological Strengths
- Large, multicentre, global randomised phase 3a design with treat‑to‑target titration.
- Predefined efficacy endpoint (HbA1c change) with adequate 52‑week follow‑up.
Limitations
- Open‑label design may introduce performance and detection bias.
- Industry funding; longer‑term durability and hard outcomes beyond 52 weeks not reported in the abstract.
Future Directions: Assess long‑term durability, cardiovascular and renal outcomes, hypoglycaemia and weight effects, and real‑world adherence/cost‑effectiveness of once‑weekly fixed‑ratio therapy.
BACKGROUND: IcoSema is a once‑weekly combination therapy of basal insulin icodec (icodec) and semaglutide (a GLP‑1 analogue) currently in development. COMBINE 1 compared the efficacy and safety of IcoSema with once‑weekly icodec alone in adults with inadequately controlled type 2 diabetes on daily basal insulin therapy. METHODS: COMBINE 1, a 52‑week, open‑label, treat‑to‑target, randomised, phase 3a trial, was done at 192 outpatient clinics and hospital departments across 20 countries and regions. Individuals aged 18 years or older with a BMI of 40 kg/m FINDINGS: Between June 1, 2022, and March 13, 2023, 1671 individuals were screened, of whom 1291 (mean age 60·6 years [SD 10·3]; 799 [62%] males and 492 [38%] females) were randomly assigned to IcoSema (n=646) or icodec (n=645). At week 52, from a baseline value of 8·22% (SD 0·83; 66·3 mmol/mol [9·1]), estimated mean change in HbA INTERPRETATION: In adults with inadequately controlled type 2 diabetes on daily basal insulin therapy, once‑weekly IcoSema showed superiority to once-weekly icodec alone in changes in HbA FUNDING: Novo Nordisk. TRANSLATIONS: For the Chinese and Japanese translations of the abstract see Supplementary Materials section.
2. Once-weekly IcoSema versus multiple daily insulin injections in type 2 diabetes management (COMBINE 3): an open-label, multicentre, treat-to-target, non-inferiority, randomised, phase 3a trial.
In this 52‑week, open‑label, treat‑to‑target, non‑inferiority, phase 3a RCT across 14 countries (n=679), once‑weekly IcoSema achieved non‑inferior HbA1c reduction versus basal‑bolus therapy in adults with type 2 diabetes inadequately controlled on daily basal insulin. The findings support regimen simplification with once‑weekly fixed‑ratio therapy.
Impact: Shows that a once‑weekly fixed‑ratio insulin–GLP‑1RA can match basal‑bolus therapy for glycaemic control, indicating potential to replace more complex multi‑daily injection regimens.
Clinical Implications: Clinicians may consider switching eligible patients from basal‑bolus to once‑weekly IcoSema to reduce treatment burden while maintaining glycaemic targets, pending individual risk‑benefit assessment.
Key Findings
- 52‑week, open‑label, treat‑to‑target, non‑inferiority, randomised phase 3a trial across 109 sites in 14 countries.
- 679 participants randomized: IcoSema (n=340) vs basal‑bolus therapy (n=339).
- IcoSema achieved non‑inferior HbA1c change at week 52 versus basal‑bolus therapy.
Methodological Strengths
- Rigorous non‑inferiority RCT with treat‑to‑target titration and 52‑week follow‑up.
- Multinational, multicentre design enhances external validity.
Limitations
- Open‑label design; potential bias cannot be excluded.
- Abstract does not report detailed safety, hypoglycaemia, or weight outcomes.
Future Directions: Compare patient‑reported outcomes, adherence, hypoglycaemia, and weight changes; evaluate long‑term cardiovascular and renal outcomes versus basal‑bolus therapy.
BACKGROUND: IcoSema is a once-weekly combination therapy of basal insulin icodec (icodec) and semaglutide (a GLP-1 analogue) developed for the treatment of type 2 diabetes. We aimed to evaluate the efficacy and safety of IcoSema versus basal-bolus therapy (BBT) in adults with type 2 diabetes inadequately controlled on daily basal insulin. METHODS: COMBINE 3, a 52-week, open-label, treat-to-target, non-inferiority, randomised, phase 3a trial, was done across 109 outpatient clinics and hospital departments in 14 countries. Individuals aged 18 years or older with type 2 diabetes (HbA FINDINGS: Between Nov 30, 2021, and Sept 28, 2022, 844 participants were screened; 679 (mean age 59·6 years [SD 10·4]; 399 [59%] males and 280 [41%] females) were randomly assigned to IcoSema (n=340) or BBT (n=339). At week 52, estimated mean change in HbA INTERPRETATION: Once-weekly IcoSema achieved non-inferior HbA FUNDING: Novo Nordisk.
3. Genetic and physiological insights into satiation variability predict responses to obesity treatment.
Using multimodal phenotyping (ad libitum CTS, calorimetry, imaging, hormones, gastric emptying), the study shows that standard clinical and hormonal factors explain only part of satiation variability in adults with obesity. A machine‑learning‑assisted genetic risk score was developed to capture residual variability, with potential to predict responses to obesity treatments.
Impact: Introduces a mechanistically grounded genetic score for satiation that may enable precision obesity medicine by predicting who benefits from specific treatments.
Clinical Implications: If validated, the genetic score and physiological profiling could guide selection of anti‑obesity interventions (e.g., pharmacotherapy or endoscopic/surgical options) tailored to individual satiation phenotypes.
Key Findings
- Quantified calories to satiation (CTS) via ad libitum meal with comprehensive physiological and behavioral assessments.
- Baseline characteristics, body composition, and hormones explained only part of CTS variability.
- Developed a machine‑learning‑assisted genetic risk score to account for remaining inter‑individual variability and predict treatment responses.
Methodological Strengths
- Multimodal phenotyping combining calorimetry, imaging, hormonal profiling, and gastric emptying tests.
- Use of machine learning to integrate genetic data with physiological measures.
Limitations
- Abstract lacks full details on sample size and external validation of the genetic score.
- Observational and modelling nature limits immediate clinical adoption without prospective validation.
Future Directions: Prospective validation of the genetic score across diverse cohorts, testing predictive utility for specific anti‑obesity therapies, and integration into clinical decision tools.
Satiation, the process that regulates meal size and termination, varies widely among adults with obesity. To better understand and leverage this variability, we assessed calories to satiation (CTS) through an ad libitum meal, combined with physiological and behavioral evaluations, including calorimetry, imaging, blood sampling, and gastric emptying tests. Although factors like baseline characteristics, body composition, and hormone levels partially explain CTS variability, they leave substantial variability unaccounted for. To address this gap, we developed a machine-learning-assisted genetic risk score (CTS